Synchronizing of animal oestrus and intra vaginal devices useful therein

ABSTRACT

An intra vaginal device which is of a variable geometry and which includes a silicone matrix impregnated with progesterone, the confirmation and content of the progesterone impregnated matrix being such as to optimize effectiveness with a lower initial loading of progesterone.

TECHNICAL FIELD

The present invention relates to improvements in and/or relating to thesynchronising of animal oestrus and intra vaginal devices useful thereintogether with related means and methods.

BACKGROUND ART

It is useful for farmers to synchronise the oestrus of animals whetherthey be cattle beasts (whether for dairy or beef purposes) sheep, goats,horses, or the like where artificial insemination is practised. By wayof example, in relation to cattle beasts, in a normal 365 day year 282days on average is taken up of the year with the gestation perioditself. With approximately 30 days to recover after delivery of itsprogeny each cow therefore has an average of only two and a half cyclesif there is to be a timely management of the herd. Thus it is importantover that remaining period of less than 53 days to ensure each cow in aherd becomes pregnant.

The traditional method of mating dairy cows with bulls is now largelysuperseded by the use of artificial insemination procedures which offerthe prospect of rapid herd improvements although bulls are stillpresented to the herd frequently to catch those animals that have notconceived by the artificial insemination procedure.

There is therefore a great advantage attached to bringing such herdanimals into oestrus simultaneously so as to make it easier to ensureeffective usage of the artificial insemination procedure andsubsequently to enable still within the “window” a further prospect ofartificial insemination of those animals synchronistically brought tooestrus that have not already conceived.

Various means of achieving such a management of the synchronisation ofthe coming into oestrus of cows (whether heifers or lactating cows) andeven sheep and goats has been disclosed in the art which includes the“EAZI-BREED CIDR Controlled Breeding and Reproductive Management”booklet made available to interested parties by InterAg a division ofthe applicant company in respect of its intra vaginal Eazi-Breed™CIDR^(R) product line.

The disclosures in the aforementioned publication, the fill contents ofwhich are here included by way of reference, comprehensively describetreatment protocols applicable at least to New Zealand herds of cattlebeasts for synchronising oestrus and treatment of anoestrus.

These treatment protocols often utilise Eazi-Breed™ CIDR^(R) devices incombination with drugs such as prostaglandin and/or oestradiol benzoate,and extend in general for periods of 7, 10 or 12 days.

If both control of the oestrus cycle and high fertility are to beoptimised in cattle, studies have shown that an intra vaginal devicemust deliver sufficient progesterone (when used with combination drugsi.e. oestradiol or GnRH) to produce a minimum plasma progesteroneconcentration of 2 ng/mL over the terminal period of treatment (1,2).

1. Kesner, J. S., Padmanabhan, V. and Convey, E. M. Biol. Reprod. 26(1982) 571-578.

2. Kinder, J. E., Kojima, F. N., Bergfeld, E. G. M., Wehrman, M. E. andFike, K. E. J.Anim. Sci 74 (1996) 1424-1440.

A cost factor arises in the adoption of such protocols as a farmer isfaced with the costs of the intra vaginal progesterone containing deviceas well as the use of the combination drugs. This ignores also theeconomic cost of the artificial breeding materials themselves.

The intra vaginal progesterone containing devices hitherto used in NewZealand and to a large extent elsewhere are typified by the CIDR^(R)product of the applicant company depicted hereinafter in FIG. 1 being avariable geometry device for vaginal insertion and retention whichcomprises a structural frame of a metal or appropnate plastics materialencased in a progesterone impregnated plastics material from which thematerial can leach in the vaginal environment and from which it can betimely withdrawn by appropriate means (e.g: a string, tail or a tool) toallow the animal to progress into oestus shortly after the removal.Hereinafter the aforementioned device will be referred to by itsregistered trademark CIDR^(R).

Another product available in the market place of this kind is anothervariable geometry device and such a device is depicted hereinafter inFIG. 2. Such a device is a helical coil capable of being helicallytightened and which is retainable in its helical form in the animalsvagina. The device includes a withdrawal cord and carries a gelatinecapsule which includes oestradiol benzoate so that there can beco-administration of the progesterone to be released over a protractedperiod and the oestradiol benzoate which is to be released at adifferent rate. Such a device includes a progesterone impregnatedplastics matrix about a helical spine. Such a device is available fromSanofi Animal Health Limited, PO Box 209, Rhodes Way, Watford, Herts,WD24QE, England under its registered trademark PRID^(R).

The aforementioned CIDR^(R) and PRID^(R) devices are manufactured inlarge volumes with the most expensive material being the progesteroneactive ingredient and thus small reductions in the progesteroneinclusion in such devices will provide an economic advantage to aproducer and to a farmer. Also any such reduction provides a reducedrisk to the environment owing to a likely reduced residual amount of theprogesterone in the matrix after the device has been withdrawn from ananimal. This reduced residual amount not only provides safety but alsodis-encourages the unrecommended reuse of a device in another animalwhere the unknown condition of such a device will give unpredictableresults.

The CIDR^(R) prior art device of the applicant company has been marketedwith a silicone plastics matrix about its spine which contains about 1.9grams of progesterone (USP) which drops to 1.33 grams still retained inthe silicone matrix if the device is withdrawn after seven days. Thesame device drops to 1.05 grams of progesterone if it is not withdrawnuntil after 12 days.

The PRID^(R) coil intra vaginal device contains at the outset 1.55 gramsof progesterone which reduces down to 1.18 grams after 7 days and downto 0.94 grams after 10 days. The leach rate from the PRID^(R) productmay be affected in part by the inclusion of inorganic materials in thesilicone plastics material such as calcium carbonate. The CIDR^(R)silicone matrix is largely free of any such inclusions.

Hoechst U.S. Pat. No. 5,398,698 discloses the use of milled sheets ofsilicone rubber in intra-vaginal devices which carry progesterone. Themilled sheets (2 to 10 mm thick) are vulcanised for from 4 to 8 minutesat from 70° C. to 120° C.

The accepted test for the delivery of progesterone or its metabolites tothe appropriate site of action in order to postpone oestrus is byreference to the progesterone level in the blood plasma of the animal.The design of such devices has to date usually been on the basis of anacceptance of the Higuchi equation based on a square root of time model(see hereinafter) which suggests that progesterone inclusions in such aplastics matrix would achieve plasma levels which decline with time.

Our investigations have found surprisingly that it is inappropriate inthe design of such intra vaginal devices to rely upon the Higuchiequation or the square root of time model. In our device release isconstant with time up to 7 days resulting in constant steady stateplasma levels over that time period.

We have determined that by modifying the levels of progesteroneinitially in a silicone matrix, by controlling the thickness of thesilicone matrix over the spine and by giving attention to the surfacearea of the device savings to a manufacturer arising from reducedquantities of progesterone being needed while at the same time achievingthe same blood levels can be achieved. Savings are also achieved overthe prior art devices in terms of the amount of silicone used, sincesilicone is the second-most costly material used in the devices, withcorresponding benefits being able to be passed on to the user.

The present invention relates to intra vaginal devices, methods ofproducing intra vaginal devices, and the use of such intra vaginaldevices for managing oestrus and for the treatment of anoestrus incattle, sheep, deer and goats.

DISCLOSURE OF INVENTION

In one aspect the invention is an intra vaginal device of a variablegeometry kind capable of being applied into the vaginal cavity of ananimal selected from the group consisting of cattle, sheep, deer andgoats, retainable therein over a period of time within the range of from7 to 12 days and then to be withdrawable therefrom to allow the onset ofoestrus, said device being characterised in that:

a matrix of a cured silicone rubber material that includes greater than5% by weight progesterone to the weight of the matrix defines anexterior surface (which may be all or part only of the device) of atleast 75 cm² contactable once inserted in the vagina of such an animalby the vaginal membrane and/or vaginal fluid(s) of the animal,

the matrix of progesterone containing silicone rubber material has beenformed by injection of the uncured progesterone containing matrix as aliquid into a mould for a sufficient time to achieve at a mouldtemperature or temperatures within the range of from 100° C. to 210° C.and a shape retaining at least partial cure thereof,

the total progesterone load (irrespective of whether alpha or betaprogesterone or mixtures thereof) being from 1 to 1.5 grams within saidmatrix,

said surface area is available to at least substantially all of thematrix for progesterone release over a thickness of no greater thanabout 1 millimeter, and

said device upon vaginal insertion into such an animal is able toachieve and then maintain in the animal for a least seven days a minimumprogesterone blood plasma level of 2 nanograms per milliliter of plasmaof the animal and which after seven days of insertion will have aresidual load in the silicone rubber matrix of less than 65% by weightof its progesterone load at insertion.

Preferably said exterior surface is from 100 to 150 cm², more preferably120 to 125 cm².

Preferably said matrix has about 10% by weight progesterone by weight ofprogesterone to the weight of matrix.

Preferably said matrix at least in part encases a deformable frame.

Preferably said frame is resilient.

Preferably said frame is substantially in the form of a “T” with thearms of the “T” being deformable to allow introduction into the vaginaof an animal, the “T” form being defined by a resilient spine aboutwhich (at least in part) there is moulded said matrix.

Preferably said frame is of nylon.

Preferably after seven days from insertion the matrix will have aresidual load of less than 60% by weight of its progesterone load atinsertion.

In a further aspect the invention is an intra vaginal device of avariable geometry kind capable of being applied into the vaginal cavityof an animal selected from the group consisting of cattle, sheep, deerand goats, retainable therein over a period of time within the range offrom 7 to 12 days and then to be withdrawable therefrom to allow theonset of oestrus, said device being characterised in that

on a frame or spine (hereafter “frame”) of variable geometry there is amatrix of a cured silicone rubber material that includes greater than 5%and less than 20% by weight progesterone to the weight of the matrixdefines and exterior surface (which may be all or part only of thedevice) of at least 100 cm² contactable once inserted in the vagina ofsuch an animal by the vaginal membrane and/or vaginal fluid(s) of theanimal,

the matrix of progesterone containing silicone rubber material has beenformed by injection of the uncured progesterone containing matrix as aliquid into a mould for a sufficient time to achieve at a mouldtemperature of temperatures within the range of from 190° C. to 195° C.and a shape retaining at least partial cure thereof,

the total progesterone load (irrespective of whether alpha or betaprogesterone or mixtures thereof) being from 1 to 1.5 grams (preferablyabout 1.35 grams) within said matrix,

said surface area is available to at least substantially all of thematrix for progesterone release over a thickness of no greater thanabout 1 millimeter, and

said device upon vaginal insertion into such an animal is able toachieve and then maintain in the animal for at least seven days aminimum progesterone blood plasma level of 2 nanograms per milliliter ofplasma of the animal and which after seven days from insertion will havea residual load in the silicone rubber matrix of less than 65% by weightof its progesterone load at insertion.

Preferably said device is substantially as herein defined with referenceto any one or more of the accompanying drawings.

In still a further aspect the invention a method of postponing oestrusor treatment of anoestrus in an animal which includes the steps of

administering into said animal by means of an intra vaginal devicesufficient progesterone from a progesterone impregnated silicone rubbermatrix where the progesterone content in the matrix is 5% or greater byweight via a surface area greater than 75 cm² so as to achieve on thelast few days of insertion a progesterone blood plasma level of greaterthan 2 nanograms per milliliter, and

removing the device after an insertion period of from 7 to 12 days.

Preferably said device is as previously defined.

Preferably said method includes the administration of oestradiol at ornear the time of insertion of said device.

Preferably said method includes the administration of a prostaglandin atabout day 6 of about a 7 to 10 day device insertion period.

In still a further aspect the invention is, in a method of attempting tosynchronise the onset of oestrus of a herd of cattle beasts, theprocedure of

administering intra vaginally to each animal of the herd progesteronefrom an intra vaginal device of the present invention and

after an appropriate period of time removing such devices to allow theonset of oestrus (the procedure optionally including the steps ofadministration of oestradiol benzoate and/or prostaglandin etc. as knownin the art or otherwise), said method being further characterised inthat levels of progesterone in the blood plasma of each animal isgreater than 2 nanograms per milliliter until such time as the devicesare withdrawn.

In still a further aspect the invention consists in a method ofsynchronising the onset of oestrus in a herd of cattle beasts whichcomprises

administering by means of an intra vaginal device to each animal from aprogesterone impregnated matrix of the device an effective amount ofprogesterone for the period the device is retained intra vaginally, thedevice having being administered with a progesterone quantity of about1.35 grams and being removed with a progesterone quantity of the orderof about 0.85 grams.

As used here in “surface area” of the progesterone impregnated matrix isthat area directly contactable by vaginal fluid(s) and/or membrane.

As used herein “surface area” is independent of any surface area of thespine (if any) which may or may not be of a plastics material. However,thicknesses of the progesterone impregnated medium or matrix are to thesurface of the spine.

While reference has been made to cattle beasts the device and method isbelieved to be equally applicable to other mammals, e.g. sheep, goat,horse, etc.

BRIEF DESCRIPTION OF DRAWINGS

The present invention will now be described with reference to theaccompanying drawings in which:

FIG. 1 shows a series of drawings (a) through (e) of a prior artEaziBreed™ CIDR™ product of this company having a progesteroneimpregnated silicone matrix of an average depth of about 1.5 mm buthaving the depth thereof varying greatly,

FIG. 1A is an elevation of the “T” shaped device capable of having thetop arms thereof resiliently bent to alongside the upstanding bodyduring insertion with an appropriate applicator pull and capable ofassuming some return to the “T” form so as to be retained within thevagina of an appropriate animal such as a cattle beast,

FIG. 1B is a section at “FF” of the top arms of the “T” form,

FIG. 1C is a section at “DD” of the body,

FIG. 1D is a view “CC” of the end of the body showing a slot formedtherein from a hole through the body so as to allow the lying therein ofa retained withdrawal string or other device,

FIG. 1E is a section of the body at “EE”.

FIG. 1′ shows the preferred spine of the prior art device, a spine whichwith no or little modification is useful in a device in accordance withthe present invention,

FIG. 1′A shows an elevation of the spine,

FIG. 1′B showing a side elevation of the spine,

FIG. 1′C showing the plan view of the top arms of the device,

FIG. 1′D shows the section at “AA”,

FIG. 1′E shows the section at “BB”,

FIG. 2 shows the PRID™ device previously referred to,

FIG. 3 shows a preferred device in accordance with the present inventionhaving an average progesterone impregnated matrix of about or less than1 mm thick over a spine of a kind shown in FIG. 1′,

FIG. 3A shows an elevation of the (CIDR-B™) device in accordance withthe present invention,

FIG. 3B shows the side elevation of the device of FIG. 3A,

FIG. 3C shows a plan view of the top of the device as shown in FIGS. 3Aand 3B,

FIG. 3D shows a section at “DD” of FIG. 3A,

FIG. 3E shows a section at “CC” of FIG. 3A,

FIG. 3F shows a section at “BB” of FIG. 3A,

FIG. 3G shows a section at “AA” of FIG. 3A,

FIG. 3H shows a section at “PP” of FIG. 3A, being the hinging region ofthe arms from the body, and

FIG. 3I is the section “HH” of FIG. 3A, and

FIGS. 4 through 15 show results, plots, models and concepts hereinafterdescribed in greater detail.

DETAILED DESCRIPTION

The device of the present invention will now be described with referenceto both in vitro and in vivo studies. In the following description thereference to the CIDR™ device is by reference to the device of the formdepicted in FIGS. 1A to 1E. The reference hereafter to the device of thepresent invention (to be known as the CIDR-B™ device) is preferably thatsubstantially as depicted in FIGS. 3A through 3I and describedhereinafter in more detail.

In Vitro Studies

The in vitro release assessment method for the existing CIDR™ device wasbased on the equipment and general procedures documented in the USPharmacopoeia, XXIII pp 1791-1975 (1995). In vitro release ofprogesterone from the device followed a declining profile with time(FIG. 4).

Mechanism of Release

Release data was plotted as cumulative amount of progesterone releasedper unit area versus square-root-of-time. The release profile overgreater than 75% of total release from the existing CIDR™ devicefollowed a square-root-of-time model (FIG. 5; linear dependence ofprogesterone release as a function of the square root of time).

Effect of Drug Load

Release rate was observed to be affected by initial drug load asexpected from the square-root-of-time model (FIG. 6: linear dependenceof progesterone release rate as a function of the square root of twicethe amount of initial drug load).

Determination of the Depletion Zone within Silicone

Depletion zone determinations clearly showed the formation of adepletion zone in the silicone skin (FIG. 7) which is consistent withthe square-root-of-time theory (FIG. 8).

The results of all in vitro experiments conducted on the CIDR™ devicesuggested that progesterone was being released from the silicone matrixaccording to the square-root-of-time model of release.

In Vivo Studies

The following in vivo studies which led to our discoveries wereconducted on the existing CIDR™ device and on devices of the presentinvention (i.e., devices referred to as the CIDR-B™ devices).

Blood level Parameter (Steady-state Blood Level)

Following insertion of the existing CIDR™ device into ovariectomizedcattle a characteristic plasma profile was observed (FIG. 9). There wasa rapid absorption phase. Blood levels peaked within a few hours. Thepeak level was sustained for 48 hours before it fell over the following24 to 48 hours to levels which were constant or diminished only veryslightly over the remaining 4 days of the 7 day insertion period(apparent steady-state levels). Following removal of the device, plasmalevels fell rapidly to basal levels. Based on FIG. 9 we selected averageprogesterone steady-state plasma levels over the last four days of a 7day insertion period as the performance indicator of the device.

Effect of Initial Progesterone Concentration

The effect of initial progesterone concentration in the device on theaverage progesterone steady-state plasma levels over the last four daysof a 7 day insertion period is shown in FIG. 10. FIG. 10 shows that thedevices containing above a 5% w/w initial progesterone concentrationproduce average progesterone steady-state plasma levels over the lastfour days of a 7 day insertion period above 2 ng/mL.

Effect of Surface Area

The effect of surface area upon the average progesterone steady-stateplasma levels over the last four days of a 7 day insertion period isshown in FIG. 11. An increase in surface area produced an increase inaverage progesterone steady-state plasma levels over the last four daysof a 7 day insertion period (FIG. 11). A surface area of greater than 75cm² is required to ensure that average progesterone steady-state plasmalevels over the last four days of a 7 day insertion period are above 2ng/mL.

Determination of the Depletion Zone within Silicone of Used Devices

Progesterone concentration at various depths of a spent existing devicethat had been inserted for 7 days in cattle is shown in FIG. 12. FIG. 12shows clearly that no distinct depletion zone was apparent followingremoval of the device after a 7 day insertion period in the vagina ofcattle (cf. the clear depletion zone which was observed in the in vitroexperiments; FIG. 7). Indeed following in vivo insertion the 0-0.5 mmoutermost layer of silicone rubber skin still contained drug but at aconcentration less than that originally incorporated into the device,the 0.5-1.0 mm layer also still contained drug but at a concentrationless than that originally incorporated into the device. Beyond 1 mm theoriginal amount of progesterone incorporated into the device wasdetected (FIG. 12). These results (FIG. 12) clearly demonstrate thatprogesterone was only eluted out of the first 1 mm of silicone rubberskin. The results also suggest that no distinct depletion zone forms asthe drug is being released while the device is inside the animal butinstead as release occurs a gradation of solid particles forms withinthe first 1 mm of skin. Possible reasons why such observations weredetected are shown in FIG. 13. These observations are not consistentwith the square-root-of-time model. Indeed, the in vivo release ofprogesterone from the device was observed to be constant with time (FIG.14) and follow a zero-order release mechanism (cf. the declining profilewhen the amount of progesterone released from the CIDR-B in vitro wasplotted against time; FIG. 4).

Investigations on a Device of the Present Invention

From these studies a device was manufactured which had a uniformsilicone rubber skin thickness of <1 mm, surface area of 120 cm² andinitially contained 1.25 g (10% w/w) of progesterone. FIG. 15 shows theaverage progesterone steady-state plasma levels over the last four daysof a 7 day insertion period determined for the existing CIDR device anda device in accordance with the present invention (CIDR-B device). FIG.15 clearly shows that the CIDR-B device is able to effectively sustainprogesterone steady-state plasma levels over the last four days of a 7day insertion period above 2 ng/mL. In addition, the final:initialcontent ratio for the CIDR-B device is less than 60% following a 7 dayinsertion period (Table 1).

TABLE 1 Comparison of the initial amount of progesterone, residualprogesterone in spent devices and amount of progesterone released fromexisting CIDR ™ device and device (CIDR-B ™ device) which hascharacteristics described in this patent application following removalafter 7 days. Initial Initial amount Residual amount Amount ofprogesterone of of progesterone progesterone Intra vaginal concentrationprogesterone remaining in released over 7 progesterone in device indevice device days Final:Initial release device (% w/w) (g) (g) (g)ratio Existing CIDR ™ 10 1.92 1.36 0.56 0.71 device Device of the 101.25 1.36 ™ 0.56 0.59 present invention (CIDR-B ™)

The following table of in vivo comparative data compares a device inaccordance with the present invention (CIDR-B™) with a CIDR™ device anda PRID™ device.

In Vivo Comparisons

Existing New CIDR-B ™ CIDR ™ device PRID ™ Parameter device (Presentinvention) DEVICE At least 10% Yes (10%) Yes (10%) No Progesterone inskin (Approx. 7.5%) Progesterone Yes Yes Yes bloods > 2 ng/mL for atleast 7 days Initial Progesterone (g) 1.9  1.35 1.55 Final Progesterone1.3  0.8 1.18 (7 days) Final Progesterone 1.18 0.63 0.94 (10 days)Final/Initial (7 days) 0.68 0.59 0.76 Final/Initial (10 days) 0.62 0.470.61 Skin thickness (mm) Variable 1.0 1.0 (0.9-5) Surface area (cm²) 120120 220

The Device of the Present Invention (CIDR-B™)

The device (CIDR-B™) consists of a progesterone impregnated siliconeelastomer skin moulded over an inert nylon spine. The active ingredientof the device is micronised USP natural progesterone. Device potency isdetermined by the percentage of active ingredient present in theinactive silicone elastomer.

The progesterone is mixed into each of two liquid silicone parts priorto the silicone being introduced to the machine for moulding. Theprogesterone is preferably mixed in at 10% by total weight.

At the moulding stage the two parts of the liquid silicone are pumpedunder pressure of approximately 100 bar from pails into the injectionchambers of an injection moulding machine. Upon injection, the two partsof silicone are simultaneously forced through a static mixer beforeflowing into an electrically heated mould.

The nylon spine is inserted into the mould prior to the silicone beinginjected. The mould has a die surface temperature of typically 190°-195°C., but preferably never exceeding 200° C. The mould is kept clampedshut under approximately 30 tonnes of static pressure while the siliconecures. At the indicated temperature and pressure, the liquid siliconetakes approximately 50 seconds to cure into a rubber.

Following curing, the finished product is removed from the mould andcooled before packaging.

The surface area of the silicone skin is approximately 120-125 cm² withthe typical formulation for the device being:

Nominal Outer Skin Weight Percentage of Percentage of (ImpregnatedMatrix) (gm) Skin Device Active progesterone USP 1.35 10% 5.1% Inactivesilicone elastomer 12.15 90% 45.9%

What we claim is:
 1. An intra vaginal device for insertion into avaginal cavity of an animal selected from the group consisting ofcattle, sheep, deer and goats, retainable therein over a period of timewithin a range of from 7 to 12 days and then to be withdrawabletherefrom to allow the onset of oestrus, said device comprising: amatrix of a cured silicone rubber material including greater than 5% byweight progesterone to a weight of the matrix and defining an exteriorsurface of at least 75 cm² contactable upon insertion in the vagina ofan animal by biological fluids of the animal, a total progesterone loadbeing from 1 to 1.5 grams within said matrix, said exterior surfacebeing at least substantially all available for progesterone release andsaid exterior surface having said progesterone load having a thicknessof less than 1 millimeter, and said matrix, upon vaginal insertion in ananimal, achieving and then maintaining, for at least seven days, aminimum progesterone blood plasma level of 2 nanograms per milliliter ofplasma of the animal and after seven days from insertion having aresidual load in the matrix of less than 65% by weight of the totalprogesterone load at insertion.
 2. The device of claim 1, wherein saidexterior surface is from 100 to 1500 cm².
 3. The device of claim 1,wherein said matrix has about 10% by weight progesterone to the weightof the matrix.
 4. The device of claim 1, wherein said matrix, at leastin part, encases a deformable frame.
 5. The device of claim 4, whereinsaid frame is resilient.
 6. The device of claim 5, wherein said frame issubstantially in a form of a “T” with the arms of the “T” beingdeformable to allow introduction into the vagina of an animal, the “T”form being defined by a resilient spine about which at least in part,there is moulded said matrix.
 7. The device of claim 4, wherein saidframe is of nylon.
 8. An intra vaginal device for insertion into avaginal cavity of an animal selected from the group consisting ofcattle, sheep, deer and goats, retainable therein over a period of timewithin a range of from 7 to 12 days and then to be withdrawabletherefrom to allow the onset of oestrus, said device comprising: a framehaving a matrix of a cured silicone rubber material including greaterthan 5% and less than 20% by weight progesterone to a weight of thematrix, the matrix defining an exterior surface of at least 100 cm²contactable upon insertion in the vagina of an animal by biologicalfluids of the animal, a total progesterone load being from 1 to 1.5grams within said matrix, said exterior surface being at leastsubstantially all available for progesterone release and said exteriorsurface having said progesterone load having a thickness of less than 1millimeter, and said matrix, upon vaginal insertion into an animal,achieving and then maintaining, for at least seven days, a minimumprogesterone blood plasma level of 2 nanograms per milliliter of plasmaof the animal and after seven days from insertion having a residual loadin the matrix of less than 60% by weight of the total progesterone loadat insertion.
 9. An intra vaginal device for insertion in a vaginalcavity of an animal selected from the group consisting of cattle, sheep,deer and goats, and retainable therein over a period of time and then tobe withdrawable therefrom to allow the onset of oestrus, said devicecomprising: a matrix of cured silicone rubber material including greaterthan 5% by weight of progesterone to a weight of the matrix, said matrixhaving at least one progesterone release surface, said at least onerelease surface having a total area of at least 75 cm² contactable, onceinserted in the vagina of an animal, by the biological fluids of theanimal, substantially all of the progesterone within the matrix beingwithin about 1 millimeter of said at least one release surface, a totalprogesterone load being at least 1 gram within said matrix, said matrix,upon vaginal insertion into an animal, achieving and then maintaining inthe animal, for at least seven days, a minimum progesterone blood plasmalevel of 2 nanograms per milliliter of plasma of the animal and ifremoved after seven days from insertion having a residual progesteroneload in the silicone rubber matrix of less than 1 gram and also lessthan 65% by weight of the total progesterone load at insertion.
 10. Thedevice of claim 9, wherein the at least one progesterone release surfaceis greater than 100 cm².
 11. An intra vaginal device for insertion intoa vaginal cavity of an animal selected from the group consisting ofcattle, sheep, deer and goats, and retainable therein over a period oftime and then to be withdrawable therefrom to allow the onset ofoestrus, said device comprising a matrix of cured silicone rubbermaterial including greater than 5% by weight of progesterone to a weightof the matrix, said matrix having at least one progesterone releasesurface, said at least one release surface having a total area of atleast 75 cm² contactable, once inserted in the vagina of an animal, bythe biological fluid of the animal, the progesterone, the cured siliconerubber material and said at least one progesterone release surfaceproducing a zero-order intra vaginal release rate of progesterone fromthe matrix, substantially all of the progesterone within the matrixbeing less than 1 millimeter from said at least one progesterone releasesurface, a total progesterone load being at least 1 gram within saidmatrix, and said matrix, upon vaginal insertion into an animal,achieving and then maintaining in the animal, for at least seven days, aminimum progesterone blood plasma level of 2 nanograms per milliliter ofplasma of the animal and if removed after seven days from insertionhaving a residual load or progesterone in the silicone rubber matrix ofless than 1 gram and also less than 65% by weight of the progesteroneload at insertion.